Selective iGluR5 receptor antagonists for the treatment of neurological disorders

ABSTRACT

The present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a selective iGluR 5  receptor antagonist. The present mvention further provides novel compounds functional as selective iGluR 5  receptor antagonists as well as compositions and s cspng said selective iGluR 5  receptor antagonists.

BACKGROUND OF THE INVENTION

[0001] In the mammalian central nervous system (CNS), the transmissionof nerve impulses is controlled by the interaction between aneurotransmitter, that is released by a sending neuron, and a surfacereceptor on a receiving neuron, which causes excitation of thisreceiving neuron. L-Glutamate, which is the most abundantneurotransmitter in the CNS, mediates the major excitatory pathways inmammals, and is referred to as an excitatory amino acid (EAA). Thereceptors that respond to glutamate are called excitatory amino acidreceptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol.Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev.Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, andHonore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acidsare of great physiological importance, playing a role in a variety ofphysiological processes, such as long-term potentiation (learning andmemory), the development of synaptic plasticity, motor control,respiration, cardiovascular regulation, and sensory perception.

[0002] Excitatory amino acid receptors are classified into two generaltypes. Receptors that are directly coupled to the opening of cationchannels in the cell membrane of the neurons are termed “ionotropic.”This type of receptor has been subdivided into at least three subtypes,which are defined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainicacid (KA). Molecular biological studies have established that AMPAreceptors are composed of subunits (GluR₁-GluR₄), which can assemble toform functional ion channels. Five kainate receptors have beenidentified which are classified as either High Affinity (KA1 and KA2) orLow Affinity (GluR₅, GluR₆, and GluR₇). Bleakman et al., MolecularPharmnacology, 49, No.4, 581,(1996).

[0003] The second general type of receptor is the G-protein or secondmessenger-linked “metabotropic” excitatory amino acid receptor. Thissecond type is coupled to multiple second messenger systems that lead toenhanced phosphoinositide hydrolysis, activation of phospholipase D,increases or decreases in cAMP formation, and changes in ion channelfunction. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993).Both types of receptors appear not only to mediate normal synaptictransmission along excitatory pathways, but also to participate in themodification of synaptic connections during development and throughoutlife. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11,508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).

[0004] The excessive or inappropriate stimulation of excitatory aminoacid receptors leads to neuronal cell damage or loss by way of amechanism known as excitotoxicity. This process has been suggested tomediate neuronal degeneration in a variety of neurological disorders andconditions. The medical consequences of such neuronal degeneration makesthe abatement of these degenerative neurological processes an importanttherapeutic goal.

[0005] Excitatory amino acid excitotoxicity has been implicated in thepathophysiology of numerous neurological disorders. For example,excitotoxicity has been linked with the etiology of cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord lesions resulting from trauma or inflammation,perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. Inaddition, excitotoxicity has been implicated in chronicneurodegenerative conditions including Alzheimer's Disease, Huntington'sChorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateralsclerosis, idiopathic and drug-induced Parkinson's Disease, as well asocular damage and retinopathy. Other neurological disorders implicatedwith excitotoxicity and/or glutamate dysfunction include muscularspasticity including tremors, drug tolerance and withdrawal, brainedema, convulsive disorders including epilepsy, depression, anxiety andanxiety related disorders such as post-traumatic stress syndrome,tardive dyskinesia, and psychosis related to depression, schizophrenia,bipolar disorder, mania, and drug intoxication or addiction. Inaddition, it has also been reported that excitatory amino acidexcitotoxicity participates in the etiology of acute and chronic painstates including severe pain, intractable pain, neuropathic pain, andpost-traumatic pain.

[0006] The use of a neuroprotective agent, such as an excitatory aminoacid receptor antagonist, is believed to be useful in treating orpreventing these disorders and/or reducing the amount of neurologicaldamage associated with these disorders. Excitatory amino acid receptorantagonists may also be useful as analgesic agents.

[0007] Early theories regarding the pathophysiology of migraine havebeen dominated since 1938 by the work of Graham and Wolff (Arch. Neurol.Psychiatry, 39, 737-63 (1938)). They proposed that the cause of migraineheadache is vasodilatation of extracranial vessels. This view issupported by knowledge that ergot alkaloids and sumatriptan contractcephalic vascular smooth muscle and are effective in the treatment ofmigraine. Sumatriptan is a hydrophilic agonist at the serotonin5-HT-1-like receptors and does not cross the blood-brain barrier(Humphrey, et al., Ann. NY Acad. Sci., 600, 587-600 (1990)).Consequently, several series of compounds said to be useful for thetreatment of migraine, have been developed to optimize the 5-HT₁-likemediated vasoconstrictive activity of sum atriptan. However,sumatriptan's contraindications, including coronary vasospasm,hypertension, and angina are also products of its vasoconstrictiveactivity (Maclntyre, P. D., et al., British Journal of ClinicalPharmnacology, 34, 541-546 (1992); Chester, A. H., et al.,Cardiovascular Research, 24, 932-937 (1990); Conner, H. E., et al.,European Journal of Pharmnacology, 161, 91-94 (1990)).

[0008] While the vascular mechanism for migraine has gained wideacceptance, there is not total agreement as to its validity. Moskowitz,for example, has shown the occurrence of migraine headaches, independentof changes in vessel diameter (Cephalalgia, 12, 5-7, (1992)). It isknown that the trigeminal ganglion, and its associated nerve pathways,are associated with painful sensations from the face such as headache,in particular migraine. Moskowitz proposed that unknown triggersstimulate the trigeminal ganglia which innervate vasculature withincephalic tissue, giving rise to the release of vasoactive neuropeptidesfrom axons innervating the vasculature. These neuropeptides initiate aseries of events leading to neurogenic inflammation of the meninges, aconsequence of which is pain. This neurogenic inflamnmation is blockedby sumatriptan at doses similar to those required to treat acutemigraine in humans. However, such doses of sumatriptan, as stated, areassociated with contraindications as a result of sumatriptan's attendantvasoconstrictive properties.(see supra.)

[0009] 5-HT_(1D) receptors have been implicated as mediating theblockade of neurogenic protein extravasation. (Neurology, 43(suppl. 3),S16-S20 (1993)). In addition, it has been reported that α₂, H₃, m-opioidand somatostatin receptors may also be located on trigeminovascularfibers and may block neurogenic plasma extravasation (Matsubara et al.,Eur. J. Pharmacol., 224, 145-150 (1992)). Weinshank et al. have reportedthat sumatriptan and several ergot alkaloids have a high affinity forthe serotonin 5-HT_(1F) receptor, suggesting a role for the 5-HT_(1F)receptor in migraine (WO93/14201).

[0010] European Patent Application Publication No. 590789A1 and U.S.Pat. No. 5,446,051 and 5,670,516 disclose that certaindecahydroisoquinoline derivative compounds are AMPA receptor antagonistsand, as such, are useful in the treatment of many different conditions,including pain and migraine headache.

[0011] Recently, it has been reported that all five members of thekainate subtype, of ionotropic glutamate receptors, are expressed on rattrigeminal ganglion neurons. In particular, high levels of GluR₅ and KA2have been observed. (Sahara et al., The Journal of Neuroscience, 17(17),6611 (1997)). Simmons et al. reported that the kainate GluR₅ receptorsubtype mediates the nociceptive response to formal in in a rat model ofpersistent pain.(Neuropharmacology, 37, 25 (1998). Further, WO98/45270previously disclosed that antagonists selective for the iGluR₅ receptorare useful for the treatment of pain, including; severe, chronic,intractable, and neuropathic pain. Noteworthy is the observation thatkainate receptors have not previously been implicated in the etiology ofmigraine headache. In particular, selective iGluR₅ receptor antagonistshave not been previously reported as being useful for the treatment ofmigraine.

[0012] Surprisingly, and in accordance with this invention, Applicantshave discovered that selective antagonists of the iGluR₅ receptorsubtype are efficacious in an animal model of neurogenic inflammationand, thus, could be useful for the treatment of migraine. Suchantagonists could address a long felt need for a safe and effectivetreatment for migraine, without attending side effects. The treatment ofneurological disorders is hereby furthered.

SUMMARY OF THE INVENTION

[0013] The present invention provides a method of treating or preventingmigraine comprising administering to a patient in need thereof aneffective amount of a selective iGluR₅ receptor antagonist or apharmaceutically acceptable salt thereof.

[0014] More specifically, the present invention provides a method oftreating or preventing dural protein extravasation comprisingadministering to a patient in need thereof an effective amount of aselective iGluR₅ receptor antagonist.

[0015] In addition, the present invention provides a method of treatingor preventing migraine comprising administering to a patient in needthereof an effective amount of a compound, or combination of compounds,which possesses the activity of a selective iGluR₅ receptor antagonist.

[0016] In another embodiment, the present invention provides a method oftreating or preventing a neurological disorder, or neurodegenerativecondition, comprising administering to a patient in need thereof aneffective amount of a selective iGluR₅ receptor antagonist or apharmaceutically acceptable salt thereof. Examples of such neurologicaldisorders, or neurodegenerative conditions, include: cerebral deficitssubsequent to cardiac bypass surgery and grafting; stroke; cerebralischemia; spinal cord lesions resulting from trauma or inflammation;perinatal hypoxia; cardiac arrest; hypoglycemic neuronal damage;Alzheimer's Disease; Huntington's Chorea; inherited ataxias;AIDS-induced dementia; amyotrophic lateral sclerosis; idiopathic anddrug-induced Parkinson's Disease; ocular damage and retinopathy;muscular spasticity including tremors; drug tolerance and withdrawal;brain edema; convulsive disorders including epilepsy; depression;anxiety and anxiety related disorders such as post-traumatic stresssyndrome; tardive dyskinesia; psychosis related to depression,schizophrenia, bipolar disorder, mania, and drug intoxication oraddiction; and acute and chronic pain states including severe pain,intractable pain, neuropathic pain, and post-traumatic pain.

[0017] In a further aspect, the present invention provides a compound ofFormula I

[0018] wherein R¹ and R² are each independently H, C₁-C₂₀ alkyl, C₂-C₆alkenyl, C₁-C₆ alkylaryl, C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl, C₁-C₆alkyl-N,N-C₁-C₆ dialkylamine, C₁-C₆ alkyl-pyrrolidine, C₁-C₆alkyl-piperidine, or C₁-C₆ alkyl-morpholine; or a pharmaceuticallyacceptable salt thereof.

[0019] In yet another aspect, the present invention provides a method oftreating or preventing migraine comprising administering to a patient inneed thereof an effective amount of a compound of Formula I.

[0020] In addition, the present invention provides pharmaceuticalcompositions useful for treating or preventing migraine comprisingselective iGluR₅ receptor antagonists in combination with one or morepharmaceutically acceptable carriers, diluents, or excipients.

[0021] The present invention also provides the use of a selective iGluR₅receptor antagonist for the manufacture of a medicament for treating orpreventing migraine.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention provides a method for the treatment ofmigraine which can be demonstrated by a particular mechanism of action,inhibition of neurogenic dural protein extravasation. By treating amigraineur with a compound or composition which is a selectiveantagonist of the iGluR₅ receptor relative to other excitatory aminoacid receptors, the neurogenic extravasation which mediates migraine isinhibited without the attending side effects of agents designed tooptimize the 5-HT₁-like mediated vasoconstrictive activity ofsumatriptan. In addition, the present invention provides compoundsfunctional as selective iGluR₅ receptor antagonists as well aspharmaceutically acceptable salts, prodrugs, and compositions thereof.

[0023] The term “pharmaceutically acceptable salt” as used herein,refers to salts of the compounds provided by, or employed in the presentinvention which are substantially non-toxic to living organisms. Typicalpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with apharmaceutically acceptable mineral or organic acid or an organic orinorganic base. Such salts are known as acid addition and base additionsalts.

[0024] It will be understood by the skilled reader that most or all ofthe compounds used in the present invention are capable of formingsalts, and that the salt forms of pharmaceuticals are commonly used,often because they are more readily crystallized and purified than arethe free bases. In all cases, the use of the pharmaceuticals describedherein as salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

[0025] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

[0026] Base addition salts include those derived from inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like. Such bases useful in preparingthe salts of this invention thus include sodium hydroxide, potassiumhydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

[0027] It should be recognized that the particular counterion forming apart of any salt of this invention is usually not of a critical nature,so long as the salt as a whole is pharmacologically acceptable and aslong as the counterion does not contribute undesired qualities to thesalt as a whole.

[0028] As used herein, the term “stereoisomer” refers to a compound madeup of the same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

[0029] The term “enantiomeric enrichment” as used herein refers to theincrease in the amount of one enantiomer as compared to the other. Aconvenient method of expressing the enantiomeric enrichment achieved isthe concept of enantiomeric excess, or “ee”, which is found using thefollowing equation:${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

[0030] wherein E¹ is the amount of the first enantiomer and E² is theamount of the second enantiomer. Thus, if the initial ratio of the twoenantiomers is 50:50, such as is present in 25 a racemic mixture, and anenantiomeric enrichment sufficient to produce a final ratio of 50:30 isachieved, the ee with respect to the first enantiomer is 25%. However,if the final ratio is 90:10, the ee with respect to the first enantiomeris 80%. An ee of greater than 90% is preferred, an ee of greater than95% is most preferred and an ee of greater than 99% is most especiallypreferred. Enantiomeric enrichment is readily determined by one ofordinary skill in the art using standard techniques and procedures, suchas gas or high performance liquid chromatography with a chiral column.Choice of the appropriate chiral column, eluent and conditions necessaryto effect separation of the enantiomeric pair is well within theknowledge of one of ordinary skill in the art. In addition, theenantiomers of compounds of formula I can be resolved by one of ordinaryskill in the art using standard techniques well known in the art, suchas those described by J. Jacques, et al., “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, Inc., 1981.

[0031] The compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

[0032] The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

[0033] The specific stereoisomers and enantiomers of compounds ofFormula (I) can be prepared by one of ordinary skill in the artutilizing well known techniques and processes, such as those disclosedby Eliel and Wilen, “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution.Racemization, and by Collet and Wilen, “Enantiomers, Racemates, andResolutions”, John Wiley & Sons, Inc., 1981. For example, the specificstereoisomers and enantiomers can be prepared by stereospecificsyntheses using enantiomerically and geometrically pure, orenantiomerically or geometrically enriched starting materials. Inaddition, the specific stereoisomers and enantiomers can be resolved andrecovered by techniques such as chromatography on chiral stationaryphases, enzymatic resolution or fractional recrystallization of additionsalts formed by reagents used for that purpose.

[0034] It should also be understood by the skilled artisan that all ofthe compounds useful for the methods of the present invention areavailable for prodrug formualtion. “Prodrug” as used herein, refers tometabolically labile ester or diester derivative of the functional acidcompounds(drugs) provided by, or employed in the methods of, the presentinvention. When administered to a patient, the prodrug undergoesenzymatic and/or chemical hydrolytic cleavage in such a manner that theparent carboxylic acid (drug), or as the case may be the parentdicarboxylic acid, is released. In all cases, the use of the compoundsdescribed herein as prodrugs is contemplated, and often is preferred,and thus, the prodrugs of all of the compounds employed are encompassedin the names of the compounds herein.

[0035] As used herein the term “C₁-C₄ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 4 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

[0036] As used herein the term “C₁-C₆ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0037] As used herein the term “C₁-C₁₀ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 10 carbon atomsand includes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4-methyl-3-heptyl and the like.

[0038] As used herein the term “C₁-C₂₀ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 20 carbon atomsand includes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like.

[0039] As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and“t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butylrespectively.

[0040] As used herein the term “C₂-C₆ alkenyl” refers to a straight orbranched, monovalent, unsaturated aliphatic chain having from two to sixcarbon atoms. Typical C₂-C₆ alkenyl groups include ethenyl (also knownas vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, andthe like.

[0041] As used herein, the term “aryl” refers to monovalent carbocyclicgroup containing one or more fused or non-fused phenyl rings andincludes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and the like.

[0042] As used herein, the term “C₁-C₆ alkylaryl” refers to a straightor branched, monovalent, saturated aliphatic chain of 1 to 6 carbonatoms which has an aryl group attached to the aliphatic chain. Includedwithin the term “C₁-C₆ alkylaryl” are the following:

[0043] and the like.

[0044] As used herein the term “(C₃-C₁₀)cycloalkyl” refers to asaturated hydrocarbon ring structure containing from three to ten carbonatoms. Typical C₃-C₁₀ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. It isunderstood that “(C₃-C₈)cycloalkyl” and “(C₄-C₆)cycloalkyl” is includedwithin the term “(C₃-C₁₀)cycloalkyl”.

[0045] As used herein, the term “C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl” refersto a straight or branched, monovalent, saturated aliphatic chain of 1 to6 carbon atoms which has a (C₃-C₁₀)cycloalkyl attached to the aliphaticchain. Included within the term “C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl” are thefollowing:

[0046] and the like.

[0047] As used herein the term “N,N-C₁-C₆ dialkylamine” refers to anitrogen atom substituted with two straight or branched, monovalent,saturated aliphatic chains of 1 to 6 carbon atoms. Included within theterm “N,N-C₁-C₆ dialkylamine” are —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₂CH₃)₂, and the like.

[0048] As used herein the term “C₁-C₆ alkyl-N,N—C₁-C₆ dialkylamine”refers to straight or branched, monovalent, saturated aliphatic chain of1 to 6 carbon atoms which has an N,N-C₁-C₆ dialkylamine attached to thealiphatic chain. Included within the term “C₁-C₆ alkyl-N,N-C₁-C₆dialkylamine” are the following:

[0049] and the like.

[0050] As used herein the termn “C₁-C₆ alkyl-pyrrolidine” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a pyrrolidine attached to the aliphatic chain.Included within the scope of the term “C₁-C₆ alkyl-pyrrolidine” are thefollowing:

[0051] and the like.

[0052] As used herein the term “C₁-C₆ alkyl-piperidine” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a piperidine attached to the aliphatic chain.Included within the scope of the term “C₁-C₆ alkyl-piperidine” are thefollowing:

[0053] and the like.

[0054] As used herein the term “C₁-C₆ alkyl-morpholine” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a morpholine attached to the aliphatic chain.Included within the scope of the term “C₁-C₆ alkyl-morpholine” are thefollowing:

[0055] and the like.

[0056] The designation “

” refers to a bond that protrudes forward out of the plane of the page.

[0057] The designation “

” refers to a bond that protrudes backward out of the plane of the page.

[0058] As used herein the term “iGluR₅” refers to the kainate ionotropicglutamate receptor, subtype 5, of the larger class of excitatory aminoacid receptors.

[0059] As used herein the term “migraine” refers a disorder of thenervous system characterized by recurrent attacks of head pain (whichare not caused by a structural brain abnormalitiy such as thoseresulting from tumor or stroke), gasrointestinal disturbances, andpossibly neurological symptoms such as visual distortion. Characteristicheadaches of migraine usually last one day and are commonly accompaniedby nausea, emesis, and photophobia.

[0060] Migraine is a “chronic” condition. The term “chronic”, as usedherein, means a condition of slow progress and long continuance. Assuch, a chronic condition is treated when it is diagnosed and treatmentcontinued throughout the course of the disease. Conversely, the term“acute” means an exacerbated event or attack, of short course, followedby a period of remission. Thus, the treatment of migraine contemplatesboth acute events and chronic conditions. In an acute event, compound isadministered at the onset of symptoms and discontinued when the symptomsdisappear. As described above, a chronic condition is treated throughoutthe course of the disease.

[0061] As used herein the term “patient” refers to a mammal, such amouse, gerbil, guinea pig, rat, dog or human. It is understood, however,that the preferred patient is a human.

[0062] It is understood that the term “selective iGluR₅ receptorantagonist” as used herein, includes those excitatory amino acidreceptor antagonists which selectively bind to the iGluR₅ kainatereceptor subtype, relative to the iGluR₂ AMPA receptor subtype.

[0063] Preferably the selective iGluR₅ antagonist for use according tothe method of the present invention has a binding affinity at least 10fold greater for iGluR₅ than for iGluR₂, more preferably at least 100fold greater. It is further understood that any selective iGluR₅antagonist, as appreciated by one of ordinary skill in the art, isincluded within the scope of the methods of the present invention. Suchselective iGluR₅ receptor antagonists are readily available to, or arereadily prepared by, one of ordinary skill in the art followingrecognized procedures. Examples of selective iGluR₅ receptor antagonistsinclude, but are not limited to, the compounds provided in WO 98/45270,the entire contents of which is herein incorporated by reference.

[0064] It is further understood that the selective iGluR₅ receptorantagonists may exist as pharmaceutically acceptable salts and, as such,salts are therefore included within the scope of the present invention.

[0065] As used herein, the terms “treating” or “to treat” each mean toalleviate symptoms, eliminate the causation of resultant symptoms eitheron a temporary or permanent basis, and to prevent, slow the appearance,or reverse the progression or severity of resultant symptoms of thenamed disorder. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

[0066] As used herein the termn “effective amount” refers to the amountor dose of the compound, upon single or multiple dose administration tothe patient, which provides the desired effect in the patient underdiagnosis or treatment.

[0067] An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose of compound administered, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the degree of involvement or the severity of themigraine involved; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; the use of concomitant medication; and otherrelevant circumstances.

[0068] A typical daily dose will contain from about 0.01 mg/kg to about100 mg/kg of each compound used in the present method of treatment.Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, morepreferably from about 0.1 mg/kg to about 25 mg/kg.

[0069] The selective iGluR₅ antagonists for use according to the methodsof the present invention may be a single compound or a combination ofcompounds capable of functioning as a selective iGluR₅ receptorantagonist. For example, it may be a combination of a compound capableof functioning as an antagonist at the iGluR₅ receptor and one or moreother glutamate receptors, in combination with one or more compoundscapable of blocking its actions at the iGluR₂ receptor. It isunderstood, however, that the selective iGluR₅ antagonist for use in themethods of the present invention, is preferably a single compound.

[0070] Oral administration is a preferred route of administering thecompounds employed in the present invention whether administered alone,or as a combination of compounds capable of acting as a selective iGluR₅receptor antagonist. Oral administration, however, is not the onlyroute, nor even the only preferred route. Other preferred routes ofadministration include transdermal, percutaneous, intravenous,intramuscular, intranasal, buccal, or intrarectal routes. Where theselective iGluR₅ receptor antagonist is administered as a combination ofcompounds, one of the compounds may be administered by one route, suchas oral, and the other may be administered by the transdermal,percutaneous, intravenous, intramuscular, intranasal, buccal, orintrarectal route, as particular circumstances require. The route ofadministration may be varied in any way, limited by the physicalproperties of the compounds and the convenience of the patient and thecaregiver.

[0071] The compounds employed in the present invention may beadministered as phannaceutical compositions and, therefore,pharmaceutical compositions incorporating said compounds are importantembodiments of the present invention. Such compositions may take anyphysical form which is pharmaceutically acceptable, but orallyadministered pharmaceutical compositions are particularly preferred.Such pharmaceutical compositions contain an effective amount of aselective iGluR₅ receptor antagonist, which effective amount is relatedto the daily dose of the compound to be administered. Each dosage unitmay contain the daily dose of a given compound, or may contain afraction of the daily dose, such as one-half or one-third of the dose.The amount of each compound to be contained in each dosage unit dependson the identity of the particular compound chosen for the therapy, andother factors such as the indication for which it is given. Thepharmaceutical compositions of the present invention may be formulatedso as to provide quick, sustained, or delayed release of the activeingredient after administration to the patient by employing well knownprocedures.

[0072] Compositions are preferably formulated in a unit dosage form,each dosage containing from about 1 to about 500 mg of each compoundindividually or in a single unit dosage form, more preferably about 5 toabout 300 mg (for example 25 mg). The term “unit dosage form” refers toa physically discrete unit suitable as unitary dosages for a patient,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical carrier, diluent, or excipient.

[0073] The inert ingredients and manner of formulation of thepharmaceutical compositions are conventional. The usual methods offormulation used in pharmaceutical science may be used here. All of theusual types of compositions may be used, including tablets, chewabletablets, capsules, solutions, parenteral solutions, intranasal sprays orpowders, troches, suppositories, transdermal patches and suspensions. Ingeneral, compositions contain from about 0.5% to about 50% of thecompounds in total, depending on the desired doses and the type ofcomposition to be used. The amount of the compound, however, is bestdefined as the “effective amount”, that is, the amount of each compoundwhich provides the desired dose to the patient in need of suchtreatment. The activity of the compounds employed in the presentinvention do not depend on the nature of the composition, hence, thecompositions are chosen and formulated solely for convenience andeconomy.

[0074] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starches,powdered cellulose especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain flours,and similar edible powders.

[0075] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0076] Tablets are often coated with sugar as a flavor and sealant. Thecompounds may also be formulated as chewable tablets, by using largeamounts of pleasant-tasting substances such as mannitol in theformulation, as is now well-established practice. Instantly dissolvingtablet-like formulations are also now frequently used to assure that thepatient consumes the dosage form, and to avoid the difficulty inswallowing solid objects that bothers some patients.

[0077] A lubricant is often necessary in a tablet formulation to preventthe tablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0078] Tablet disintegrators are substances which swell when wetted tobreak up the tablet and release the compound. They include starches,clays, celluloses, algins and gums. More particularly, corn and potatostarches, methylccllulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

[0079] Enteric formulations are often used to protect an activeingredient from the strongly acid contents of the stomach. Suchformulations are created by coating a solid dosage form with a film of apolymer which is insoluble in acid environments, and soluble in basicenvironments. Exemplary films are cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate andhydroxypropyl methylcellulose acetate succinate.

[0080] When it is desired to administer the compound as a suppository,the usual bases may be used. Cocoa butter is a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use, also.

[0081] Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with innumerable poresthrough which the drugs are pumped by osmotic action.

[0082] The following table provides an illustrative list of formulationssuitable for use with the compounds employed in the present invention.The following is provided only to illustrate the invention and shouldnot be interpreted as limiting the present invention in any way.

Formulation 1

[0083] Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250    Starch,dried 200    Magnesium stearate  10    Total 460 mg

[0084] The above ingredients are mixed and filled into hard gelatincapsules in 460 mg quantities.

Formulation 2

[0085] A tablet is prepared using the ingredients below: Quantity(mg/tablet) Active Ingredient 250    Cellulose, microcrystalline 400   Silicon dioxide, fumed  10    Stearic acid  5    Total 665 mg

[0086] The components are blended and compressed to form tablets eachweighing 665 mg.

Formulation 3

[0087] An aerosol solution is prepared containing the followingcomponents: Weight % Active Ingredient 0.25 Ethanol 29.75 Propellant 2270.00 (Chlorodifluoromethane) Total 100.00

[0088] The active compound is mixed with ethanol and the mixture addedto a portion of the Propellant 22, cooled to −30° C. and transferred toa filling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

[0089] Tablets each containing 60 mg of active ingredient are made asfollows: Active Ingredient   60 mg Starch   45 mg Microcrystallinecellulose   35 mg Polyvinylpyrrolidone   4 mg Sodium carboxymethylstarch  4.5 mg Magnesium stearate  0.5 mg Talc   1 mg Total  150 mg

[0090] The active ingredient, starch, and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

Formulation 5

[0091] Capsules each containing 80 mg medicament are made as follows:Active Ingredient  80 mg Starch  59 mg Microcrystalline cellulose  59 mgMagnesium stearate  2 mg Total 200 mg

[0092] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 sieve, and filled into hard gelatincapsules in 200 mg quantities.

Formulation 6

[0093] Suppositories each containing 225 mg of active ingredient may bemade as follows: Active Ingredient   225 mg Saturated fatty acidglycerides 2,000 mg Total 2,225 mg

[0094] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

[0095] Suspensions each containing 50 mg of medicament per 5 ml dose aremade as follows: Active Ingredient   50 mg Sodium carboxymethylcellulose   50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavorq.v. Color q.v. Purified water to total   5 ml

[0096] The medicament is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with someof the water and added, with stirring. Sufficient water is then added toproduce the required volume.

Formulation 8

[0097] An intravenous formulation may be prepared as follows: ActiveIngredient 100 mg Mannitol 100 mg 5 N Sodium hydroxide 200 ml Purifiedwater to total  5 ml

[0098] It is understood by one of ordinary skill in the art that theabove procedures can also be applied to a method of treating migrainecomprising administering to a patient an effective amount of a compoundwhich possesses the activity of a selective iGiuR₅ receptor antagonist.

[0099] Inhibition of neuronal protein dural extravasation is anexemplary mechanism of action for the method of the present invention.The method further requires that compounds which exhibit suchinhibition, also demonstrate selective binding and inhibition of theiGluR5 receptor. The panel of compounds used to illustrate the principleof the present invention, and the pharmacological assays employed todemonstrate the mechanistic effectiveness of the invention, aredescribed below. It is believed that Compounds III, IV(a), and IV(b)herein, represent novel compounds and, as such, have not previously beendescribed as selective iGluR₅ receptor antagonists, nor reported asefficacious in treating migraine. Compounds III, IV(a), and IV(b)therefore, are provided as additional embodiments of the presentinvention.

[0100] The following examples illustrate the methods of the presentinvention. The reagents and starting materials are readily available toone of ordinary skill in the art. These examples are intended to beillustrative only and are not to be construed so as to limit the scopeof the invention in any way. As used herein, the following terms havethe meanings indicated: “i.v.” refers to intravenously; “p.o.” refers toorally; “i.p.” refers to intraperitoneally; “eq” or “equiv.” refers toequivalents; “g” refers to grams; “mg” refers to milligrams; “L” refersto liters; “mL” refers to milliliters; “μL” refers to microliters; “mol”refers to moles; “mmol” refers to millimoles; “psi” refers to pounds persquare inch; “mm Hg” refers to millimeters of mercury; “min” refers tominutes; “h” or “hr” refers to hours; “° C.” refers to degrees Celsius;“TLC” refers to thin layer chromatography; “HPLC” refers to highperformance liquid chromatography; “R_(f)” refers to retention factor;“R_(t)” refers to retention time; “δ” refers to part per milliondown-field from tetramethylsilane; “THF” refers to tetrahydrofuran;“DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethylsulfoxide; “aq” refers to aqueous; “EtOAc” refers to ethyl acetate;“iPrOAc” refers to isopropyl acetate; “MeOH” refers to methanol; “MTBE”refers to tert-butyl methyl ether; “RT” refers to room temperature;“K_(i)” refers to the dissociation constant of an enzyme-antagonistcomplex and serves as an index of ligand binding; and “ID₅₀” and “ID₁₀₀”refer to doses of an administered therapeutic agent which produce,respectively, a 50% and 100% reduction in a physiological response.

EXAMPLE 1 Compound I 3S, 4aR, 6S, 8aR-6-(((4-carboxy) phenyl) methyl)-1,2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid

[0101]

[0102] Those skilled in the art will recognize Compound I as anexcitatory amino acid receptor antagonist, selective for the iGluR₅receptor subtype. Compound I may be readily prepared by one of ordinaryskill in the art following recognized general procedures as described inU.S. Pat. No. 5,446,051, and more specifically as recently published ininternational application WO 98/45270, published Oct. 15, 1998.

Compound II 3S, 4aR, 6S, 8aR-6-((((1H-Tetrazole-5-yl) methyl) oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8,8a-decahydroisoquinoline-3-carboxylic acid

[0103]

[0104] Those skilled in the art will recognize Compound II as anexcitatory amino acid receptor antagonist, selective for the iGluR₅receptor subtype. Compound II may be readily prepared and resolved byone of ordinary skill in the art following recognized 10 generalprocedures as described in U.S. Pat. No. 5,670,516 (see Example No. 11,Compound No. 7), and more specifically as recently published ininternational application WO 98/45270, published Oct. 15, 1998.

[0105] Compound III represents a novel compound, functional as aselective iGluR₅ receptor antagonist. Compound m may be readilyprepared; the desired enantiomer may be optically resolved; andpharmaceutical compositions comprising Compound im may be readilyformulated by following general methods essentially as described forExample No. 8, Compound No. 8 of U.S. Pat. No. 5,670,516, the entirecontents of which is herein incorporated by reference.

Compound IV(b) 3S, 4aR, 6S, 8aR Ethyl6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4,4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate

[0106]

[0107] A. Preparation of 3S, 4aR, 6S, 8aR Ethyl6-((4-Methylphenyl)sulfonyloxy)methyl)-2-methoxycarbonyl-1, 2, 3, 4, 4a,5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate

[0108] To a solution of 15.0 g (50.1 mmol) of hydroxymethyl intermediate(See Col.11-12, Scheme II of U.S. Pat. No. 5,356,902, the entirecontents of which are herein incorporated by reference) cooled to 0° C.in CH₂Cl₂ (100 mL), was added triethylamine (20.9 mL, 150.3 mmol)followed by toluenesolfonyl chloride (19.1 g, 100.2 mmol) dissolved inCH₂Cl₂ (100 mL). The reaction was warmed to room temperature and stirred16 h, then partitioned between CH₂Cl₂ and 10% aqueous NaHSO₄. Theaqueous layer was extracted with CH₂Cl₂ and the combined organics weredried over MgSO₄, filtered, and concentrated in vacuo. Columnchromatography (10-50% EtOAc/hexane) provided 20.1 g (89%) of thedesired intermediate title compound as a colorless oil:

[0109] MS(m/e): 451.5 (M⁺)

[0110] Calculated for C₂₂H₃₁NO₇S 0.1 CH₂Cl₂: Theory: C, 57.45; H,6.81;N,

[0111] 3.03. Found: C, 57.76; H, 6.93; N, 3.35.

[0112]¹³C NMR (DMSO-d₆): δ171.4, 144.8, 132.4, 130.1, 127.6, 74.6, 60.4,

[0113] 53.1, 52.4, 44.1, 34.6, 31.8, 31.0, 29.8, 28.8, 24.9, 23.3, 21.0,14.0.

[0114] B. Preparation of 3S, 4aR, 6S, 8aR Ethyl 6-(((3S,5S)-5-(Ethoxycarbonyl)-3-hydroxypyrrolidinyl)methyl)-2-methoxycarbonyl-1,2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate

[0115] A mixture of trans 4-hydroxy-L-proline ethyl ester (6.5 g, 33.1mmol), the compound of Step A above (10.0 g, 22.0 mmol), and potassiumcarbonate (4.6 g, 33.1 mmol) were heated at reflux in acetonitrile (22mL) for 60 h. The reaction mixture was cooled to room temperature, andpartitioned between CH₂Cl₂ and water. The aqueous layer was extractedtwo times with CH₂Cl₂ and the combined organics were dried over MgSO₄,filtered, and concentrated in vacuo. Column chromatography (50%EtOAc/hexane followed by 5% MeOH/CH₂Cl₂) gave 9.2 g (95%) of the desiredintermediate title compound as a colorless oil:

[0116] MS(m/e): 441.3 (M⁺)

[0117] Calculated for C₂₂H₃₆N₂O₇S: Theory: C, 59.98; H, 8.24; N, 6.36.Found:

[0118] C, 60.17; H, 8.23; N, 6.42.

[0119] C. Preparation of 3S, 4aR, 6S, 8aR Ethyl6-(((5S)-5-(Ethoxycarbonyl)-3-oxopyrrolidinyl)methyl)-2-methoxycarbonyl-1,2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate

[0120] To a solution of DMSO (2.3 mL, 32.5 mmol) cooled to −78° C. inCH₂Cl₂ (25 mL) was added, dropwise, oxalyl chloride (1.4 mL, 16.3 mmol).The reaction mixture was stirred for 5 min, then the compound of Step Babove (6.0 g, 13.6 mmol) dissolved in 20 mL of CH₂Cl₂ was added. Uponstirring for 45 min at −78 ° C., triethylamine (9.5 mL, 32.5 mmol) wasadded. The reaction was warmed to room temperature over approximately 2hours, and quenched by the addition of 10% aqueous NaHSO₄. The aqueouslayer was extracted with CH₂Cl₂ and the combined organics were driedover MgSO₄, filtered, and concentrated in vacuo. Column chromatography(25-50% EtOAc/hexane) provided 4.6 g (78%) of the desired intermediatetitle compound as a colorless oil:

[0121] MS(m/e): 439.1 (M⁺)

[0122] D. Preparation of 3S, 4aR, 6S, 8aR Ethyl6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-2-methoxycarbonyl-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate

[0123] To a mixture of the compound of Step C above (4.62 g, 10.5 mmol)cooled to −78° C. in CH₂Cl₂ (50 mL) was added, dropwise,diethylaminosulfur trifluoride (3.5 mL, 26.3 mmol). The reaction wasallowed to warm to room temperature, stirred an additional 48 h, thenquenched by the addition of MeOH. After concentrating in vacuo, theresidue was partitioned between CH₂Cl₂ and saturated aqueous NaHCO₃. Theaqueous layer was extracted with CH₂Cl₂ and the combined organics weredried over MgSO₄, filtered, and concentrated in vacuo. Columnchromatography (25-50% EtOAc/hexane) provided 3.3 g (68%) of the desiredintermediate title compound as a colorless oil:

[0124] MS(m/e): 461.2 (M⁺)

[0125] Calculated for C₂₂H₃₄F₂N₂O₆: Theory: C, 57.38; H, 7.44; N, 6.08.Found:

[0126] C, 57.28; H, 7.52; N, 6.13.

[0127] E. Preparation of 3S, 4aR, 6S, 8aR Ethyl6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4,4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate (Compound IV(b))

[0128] A solution of the compound of Step D above (3.3 g, 7.10 mmol)dissolved in CH₂Cl₂ (40 mL) was cooled to 0° C. and charged withtrimethylsilyl iodide (3.0 mL, 21.3 mmol). The reaction was allowed towarm to room temperature, stirred an additional 4 h, then quenched bythe addition of saturated aqueous NaHCO₃ (50 mL). The aqueous layer wasextracted with CH₂Cl₂ and the combined organics washed with a 1 Nsolution of sodium thiosulfate, dried over MgSO₄, filtered, andconcentrated in vacuo. The material was chromatographed, (2%MeOH/CH₂CH₂Cl₂), dissolved in 20 mL of Et₂O, and to it was added 50 mLof a HCl/Et₂O solution. The solvent was removed in vacuo, providing 2.6g (76%) of the final title compound as a white solid:

[0129] MS(m/e): 403.4 (M⁺)

[0130] Calculated for C₂₀H₃₂ Cl₂F₂N₂O₄: Theory: C, 50.53; H, 7.21; N,5.89.

[0131] Found: C, 50.90; H, 7.41; N, 5.84.

[0132]¹³C NMR (D₂O): δ170.3, 167.7, 125.1 (t, J_(C-F)=249.1 Hz), 65.9,65.0,

[0133] 64.1, 63.4, 60.1 (t, J_(C-F)=33.9 Hz), 57.6, 52.8, 42.9, 37.2 (t,J_(C-F)=26.4

[0134] Hz), 34.5, 31.7, 31.3, 30.5, 28.4, 26.9, 24.3, 13.6.

Compound IV(a) 3S, 4aR, 6S, 8aR 6-(((2S)-2-(Carboxylicacid)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8,8a-decahydroisoquinoline-3-carboxylic Acid

[0135]

[0136] A solution of 3S, 4aR, 6S, 8aR Ethyl6-(((2S)-2-(Ethoxycarbonyl)4,4-difluoropyrrolidinyl)methyl)-2-methoxycarbonyl-1,2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate (3.3 g,7.10 mmol), the compound of Step D above, dissolved in 5 N aqueous HCl(15 mL) was heated at 90° C. for 18 h. The reaction mixture was cooledto room temperature and concentrated in vacuo. The resulting crude foamwas dissolved in water (75 mL) and stirred in the presence of Dowex 50X8(100-200) ion-exchange resin (10 g) for 2 h. The resin was filtered,washed sequentially with 1:1 THF/H₂O and water, then stirred in thepresence of 10% pyridine/H₂O for 2 h. After filtration, the resin waswashed with water, and the filtrate was concentrated in vacuo to providethe title compound (0.6 g, 97%) as a white foam:

[0137] MS(m/e): 347.2 (M⁺)

[0138] Calculated for C₁₆H₂₄F₂N₂O₄ 0.1 H₂O: Theory: C, 55.19; H, 7.01;N,

[0139] 8.05. Found: C, 54.81; H, 6.82; N, 8.13.

[0140]¹³C NMR (D₂O): δ175.1, 171.1, 125.6 (t, J_(C-F)=249.4 Hz), 67.9,63.0,

[0141] 59.3 (t, J_(C-F)=34.0 Hz), 54.5, 42.5, 37.5 (t, J_(C-F)=24.9 Hz),34.3, 32.7,

[0142] 32.4, 30.6, 28.2, 27.0, 24.3.

EXAMPLE 2

[0143] To establish that the iGluR₅ receptor subtype is mediatingneurogenic protein extravasation, a functional characteristic ofmigraine, the binding affinity of the panel compounds to the iGluR₅receptor is first measured using standard methods. For example, theactivity of compounds acting at the iGluR₅ receptor antagonists can bedetermined by radiolabelled ligand binding studies at the cloned andexpressed human iGluR5 receptor (Korczak et al., 1994, Recept. Channels3; 41-49), and by whole cell voltage clamp electrophysiologicalrecordings of currents in acutely isolated rat dorsal root ganglionneurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585). Theselectivity of compounds acting at the iGluR₅ receptor subtype can thenbe determined by comparing antagonist activity at the iGluR₅ receptorwith antagonist activity at other AMPA and kainate receptors. Methodsuseful for such comparison studies include: receptor-ligand bindingstudies and whole-cell voltage clamp electrophysiological recordings offunctional activity at human GluR_(l), GluR₂,GluR₃ and GluR₄ receptors(Fletcher et al., 1995, Recept. Channels 3; 21-31); receptor-ligandbinding studies and whole-cell voltage clamp electrophysiologicalrecordings of functional activity at human GluR₆ receptors (Hoo et al.,Recept. Channels 2;327-338); and whole-cell voltage clampelectrophysiological recordings of functional activity at AMPA receptorsin acutely isolated cerebellar Purkinje neurons (Bleakman et al., 1996,Mol. Pharmacol. 49; 581-585) and other tissues expressing AMPA receptors(Fletcher and Lodge, 1996, Pharmacol. Ther. 70; 65-89).

iGluR5 Antagonist Binding Affinity Profiles

[0144] Cell lines (HEK293 cells) stably transfected with human iGluRreceptors were employed. Displacement of ³[H] AMPA by increasingconcentrations of antagonist was measured on iGluR₁, iGluR₂, iGluR₃, andiGluR₄ expressing cells, while displacement of 3[H] kainate (KA) wasmeasured on iGluR₅, iGluR₆, iGluR₇, and KA2-expressing cells. Estimatedantagonist binding activity (K_(i)) in μM was determined for CompoundsI-IV. As an indicia of selectivity, the ratio of binding affinity to theiGluR₂ AMPA receptor subtype, versus the binding affinity to iGluR₅kainate receptor subtype, was also determined. Compounds provided by thepresent invention displayed a binding affinity of at least 10 foldgreater for iGluR₅ than that for iGluR₂, more preferably at least 100fold.

EXAMPLE 3

[0145] The following animal model was employed to determine the abilityof each of the panel of compounds to inhibit protein extravasation, anexemplary functional assay of the neuronal mechanism of migraine. Theresults obtained for the panel of compounds in this model are summarizedin Table I (infra).

Animal Model of Dural Protein Extravasation

[0146] Harlan Sprague-Dawley rats (225-325 g) or guinea pigs fromCharles River Laboratories (225-325 g) were anesthetized with sodiumpentobarbital intraperitoneally (65 mg/kg or 45 mg/kg respectively) andplaced in a stereotaxic frame (David Kopf Instruments) with the incisorbar set at −3.5 mm for rats or −4.0 mm for guinea pigs. Following amidline sagital scalp incision, two pairs of bilateral holes weredrilled through the skull (6 mm posterially, 2.0 and 4.0 mm laterally inrats; 4 mm posteriorly and 3.2 and 5.2 mm laterally in guinea pigs, allcoordinates referenced to bregma). Pairs of stainless steel stimulatingelectrodes, insulated except at the tips (Rhodes Medical Systems, Inc.),were lowered through the holes in both hemispheres to a depth of 9 mm(rats) or 10.5 mm (guinea pigs) from dura.

[0147] The femoral vein was exposed and a dose of the test compound wasinjected intravenously (i.v.) at a dosing volume of 1 ml/Kg or, in thealternative, test compound was administered orally (p.o) via gavage at avolume of 2.0 ml/Kg. Approximately 7 minutes post i.v. injection, a 50mg/Kg dose of Evans Blue, a fluorescent dye, was also injectedintravenously. The Evans Blue complexed with proteins in the blood andfunctioned as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion wasstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

[0148] Fifteen minutes following stimulation, the animals were killedand exsanguinated with 20 mL of saline. The top of the skull was removedto facilitate the collection of the dural membranes. The membranesamples were removed from both hemispheres, rinsed with water, andspread flat on microscopic slides. Once dried, the tissues werecoverslipped with a 70% glycerol/water solution.

[0149] A fluorescence microscope (Zeiss) equipped with a gratingmonchromator and a spectrophotometer was used to quantify the amount ofEvans Blue dye in each sample. An excitation wavelength of approximately535 nm was utilized and the emission intensity at 600 nm was determined.The microscope was equipped with a motorized stage and also interfacedwith a personal computer. This facilitated the computer-controlledmovement of the stage with fluorescence measurements at 25 points (500mm steps) on each dural sample. The mean and standard deviation of themeasurements were determined by the computer.

[0150] The extravasation induced by the electrical stimulation of thetrigeminal ganglion was an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio of the amount of extravasation in the dura from thestimulated side, over the amount of extravasation in the unstimulatedside, was calculated. Control animals dosed with only with saline,yielded a ratio of approximately 2.0 in rats and apprximately 1.8 inguinea pigs. In contrast, a compound which effectively prevented theextravasation in the dura from the stimulated side would yield a ratioof approximately 1.0.

[0151] Dose-response curves were generated for each of the panel ofcompounds and the dose that inhibited the extravasation by 50% (ID₅₀) or100% (ID₁₀₀) was approximated. The respective ID₅₀ and/or ID₁₀₀ values,for each of the panel of compounds employed in the present invention,are summarized in Table I below. TABLE I Inhibition of Dural ProteinExtravasation (ng/Kg) Compound Route of administration ID₅₀ (ng/Kg)ID₁₀₀ (ng/Kg) I i.v.  6.5 (rat), —  4.0 (Gpig) — II i.v   15 (rat) — Ini.v .0053 (rat) 0.10 IV(b) p.o — 0.01

What is claimed is:
 1. A method of treating migraine comprisingadministering to a patient in need thereof an effective amount of aselective iGluR₅ receptor antagonist or a pharmaceutically acceptablesalt thereof.
 2. A method of treating migraine comprising administeringto a patient in need thereof a pharmaceutical composition comprising aselective iGiuR₅ receptor antagonist in combinationwith one or morepharmaceutically acceptable carmers, diluents, or excipients.
 3. Themethod according to claim 1 wherein the selective iGluR₅ receptorantagonist is 3S, 4aR, 6S, 8aR-(((4carboxy) phenyl methyl) -1, 2, 3, 4,4a, 5, 6, 7, 8, 8a-decahydrolsoquinoline-3-carboxylic acid.
 4. Themethod according to claim 1 wherein the selective iGluR₅ receptorantagonist is 3S, 4aR, 6S, 8aR-6-((((1H-Tetrazole-5-yl) methyl) oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8,8a-decahydroisoquinoline-3-carboxylic acid.
 5. The method according toclaim 1 wherein the selective iGluR₅ receptor antagonist is a compoundof the formula

wherein R¹ and R² are each independently H, C₁-C₂₀ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkylaryl, C₁-C₈ alkyl(C₃-C₁₀)cycloalkyl, C₁-C₆ alkyl-N,N-C₁-C₆dialkylamine, C₁-C₆ alkyl-pyrrolidine, C₁-C₆ alkyl-piperidine, C₁-C₆alkyl-morpholine or a pharmaceutically acceptable salt thereof.
 6. Themethod according to claim 5 wherein the selective iGiuR₅ receptorantagonist is selected from 3S, 4aR, 68, 8aR Ethyl6-(((2S)-2-(Ethoxycabonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3.4,4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate, or 3S, 4aR, 6S,8aR 6-(((2S)-2-(Carboxylic acid)-4,4-difluoropyrrolidiny)methyl)-1, 2,3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic Acid
 7. Amethod of treating dural protein extravasation comprising administeringto a patient in need thereof an effective amount of a selective iGluR₅receptor antagonist.
 8. A method of treating migraine comprisingadministering to a patient in need thereof an effective amount of acompound, or combination thereof, which possesses the activity of aselective iGluR5 receptor antagonist.
 9. The use of a selective iGluR₅receptor antagonist for the manufacture of a medicament for treatingmigraine.
 10. The use according to claim 9 wherein the selective iGluR₅receptor antagonist is 3S, 4aR, 6S, 8aR-6-(((4carboxy) phenyl) methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid.11. The use according to claim 9 wherein the selective iGluR₅ receptorantagonist is 3S, 4aR, 6S, 8aR-6-((((1H-Tetrazole-5-yl) methyl) oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3carboxylicacid.
 12. The use according to claim 9 wherein the selective iGluR₅receptor antagonist is a compound of Formula I

wherein R¹ and R² are each independently H, C₁-C₂₀ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkylaryl, C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl, C₁-C₆ alkyl-N,N-C₁-C₆dialkylamine, C₁-C₆ alkyl-pyrrolidine, C₁-C₆ alkyl-piperidine, or C₁-C₆alkyl-morpholine; or a pharmaceutically acceptable salt thereof.
 13. Theuse according to claim 12 wherein the selective iGluR₅ receptorantagonist is selected from 3S, 4aR, 6S, 8aR Ethyl6(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4,4a, 5, 6, 7, 8, 8a-decahydrolsoquinoline-3-carboxylate, or 3S, 4aR, 6S,8aR, 6-(((2S)-2-(Carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1, 2,3, 4, 4a, 5, 6, 7, 8, 8a-decahydrolsoquinoline-3-carboxylic Acid
 14. Acompound of the formula

wherein R¹ and R² are each independently H, C₁-C₂₀ alkyl, C₂-C₆ alkenyl,C₁-C₆ alkylaryl, C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl, C₁-C₆ alkyl-N,N-C₁-C₆dialkylamine, C₁-C₆ alkyl-pyrrolidine, C₁-C₆ alkyl-piperidine, C₁-C₆alkyl-morpholine or a pharmaceutically accepatable salt thereof.
 15. Acompound according to claim 14 wherein R¹ and R² are each independentlyH or C₁-C₂₀ alkyl.
 16. A compound which is 3S, 4aR, 6S, 8aR Ethyl6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4,4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate, or apharmaceutically acceptable salt thereof.
 17. A compound which is 3S,4aR, 6S, 8aR 6-(((2S)-2-(Carboxylicacid)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8,8a-decahydroisoquinollne-3-carboxylic acid, or a pharmaceuticallyacceptable salt thereof.
 18. A pharmaceutical composition whichcomprises a compound as claimed in claim 16 in combination with one ormore pharmaceutically acceptable carriers, diluents, or excipients. 19.A pharmaceutical composition for the treatment of migraine whichcomprises a selective iGluR₅ receptor antagonist in combination with apharmaceutically acceptable carrier, diluent, or excipient.
 20. Acompound which is 3S, 4aR, 6S, 8aR Ethyl6-(((2S)2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4,4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate•mandelate.